PDCD1 and neoplasm: Binding of PD-1 to PD-L1 can cause phosphorylation of two tyrosines in the cytoplasmic domain of PD-1; phosphorylated PD-1 directly or indirectly recruits the cytoplasmic tyrosine phosphatases Shp2 and Shp1 [66, 67], thereby activating tumor proliferation and survival by terminating various downstream events such as CD28 signaling (Fig. 2).